Bupivacaine meloxicam sustained release solution based on ethyl cellulose and its preparation method and application

Abstract

The application relates to the technical field of pharmaceutical preparations, in particular to a bupivacaine meloxicam sustained-release solution based on ethyl cellulose as well as a preparation method and application thereof. The sustained-release solution comprises 2-3 parts of bupivacaine or a pharmaceutically acceptable salt thereof, 0.05-0.1 parts of meloxicam or a pharmaceutically acceptable salt thereof, 5-20 parts of ethyl cellulose, 20-45 parts of glyceryl triacetate, 30-45 parts of dimethyl sulfoxide, 0.03-0.07 parts of maleic acid and 0.03-0.07 parts of dibutylhydroxytoluene. The application takes ethyl cellulose as a core sustained-release carrier, combines a specific solvent system, and forms a uniform and stable sustained-release solution. The preparation can continuously release drugs for more than 72 hours after use, is effectively used for postoperative long-acting analgesia, and has the outstanding advantages of good biocompatibility, simple preparation process, low risk of free implementation and the like.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a bupivacaine meloxicam sustained-release solution based on ethyl cellulose, its preparation method, and its application. Background Technology

[0002] Postoperative pain is one of the major clinical problems encountered after surgery. Effective postoperative analgesia not only improves patient comfort but also facilitates early ambulation, reduces complications, and accelerates recovery. The combined use of the local anesthetic bupivacaine and the nonsteroidal anti-inflammatory drug meloxicam, which produce synergistic analgesic effects through different mechanisms of action, has become an important strategy for multimodal postoperative analgesia.

[0003] To prolong drug action time and reduce dosing frequency, sustained-release formulation technology has been extensively studied. Existing technologies often utilize biodegradable polymers such as polylactic-co-glycolic acid copolymer (PLGA), polycaprolactone (PCL), and polyorthoesters (POE) as drug carriers. For example, a technology discloses a bupivacaine and meloxicam delivery system using polyorthoesters. However, these polymers have some inherent drawbacks: degradation products of PLGA and PCL may create a localized acidic environment, causing aseptic inflammation; the synthesis and quality control of polyorthoesters are complex and costly; furthermore, these polymer systems typically require complex formulation processes (such as microsphere preparation), increasing production difficulty and cost.

[0004] Ethyl cellulose (EC) is a water-insoluble, non-toxic, and biocompatible cellulose derivative commonly used in pharmaceutical formulations as a coating material, binder, and sustained-release matrix material. It exhibits good film-forming properties and chemical stability, and can delay drug release by forming a gel matrix or diffusion barrier. However, the application of ethyl cellulose in a bupivacaine / meloxicam sustained-release solution to construct a stable, homogeneous, and long-acting release formulation has not yet been publicly reported.

[0005] Therefore, developing a novel bupivacaine-meloxicam sustained-release solution based on ethyl cellulose to address the problems of local irritation, complex processes, and high costs in existing technologies has significant clinical and market value. Summary of the Invention

[0006] The purpose of this invention is to provide a bupivacaine meloxicam sustained-release solution with simple composition, good stability, and good sustained-release effect, as well as its preparation method and application, so as to solve the problems existing in the prior art.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: One of the technical solutions of this invention provides a bupivacaine-meroxicam sustained-release solution, comprising the following components in parts by weight: 2-3 parts of bupivacaine or a pharmaceutically acceptable salt thereof, 0.05-0.1 parts of meloxicam or a pharmaceutically acceptable salt thereof, 5-20 parts of ethyl cellulose, 20-45 parts of triacetin, 30-45 parts of dimethyl sulfoxide, 0.03-0.07 parts of maleic acid, and 0.03-0.07 parts of butylated hydroxytoluene.

[0008] The second technical solution of the present invention provides a method for preparing the above-mentioned bupivacaine meloxicam sustained-release solution, comprising the following steps: (1) Ethyl cellulose and triacetin were mixed in parts by mass to obtain a polymer phase; (2) By mass fractions, bupivacaine or a pharmaceutically acceptable salt thereof, meloxicam or a pharmaceutically acceptable salt thereof, maleic acid, butylated hydroxytoluene and dimethyl sulfoxide are mixed to obtain the drug phase; (3) Mix the drug phase and the polymer phase to obtain a bupivacaine meloxicam sustained-release solution.

[0009] The third technical solution of the present invention provides the application of the above-mentioned bupivacaine meloxicam sustained-release solution in the preparation of drugs for the prevention or treatment of postoperative pain.

[0010] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention utilizes the property of ethyl cellulose to construct a gel skeleton in an aqueous environment, which effectively delays the diffusion process of the drug and achieves continuous drug release for more than 72 hours to meet the actual needs of long-acting analgesia after surgery.

[0011] (2) The butylated hydroxytoluene added to the formulation of this invention acts as an antioxidant, effectively inhibiting the oxidative degradation of bupivacaine and meloxicam during storage and extending the shelf life of the product.

[0012] (3) Ethyl cellulose in this invention is a widely recognized safe excipient that does not participate in the metabolic process in the body and is non-irritating, effectively avoiding the local acidic irritation problem that may be caused by the degradation of materials such as poly(lactic-co-glycolic acid) (PLGA). Attached Figure Description

[0013] Figure 1 The graph shows the in vitro cumulative release rate of the bupivacaine meloxicam sustained-release solution prepared in Example 1. Detailed Implementation

[0014] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0015] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0016] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0017] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be obvious to those skilled in the art. This application specification and embodiments are merely exemplary.

[0018] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0019] All room temperatures mentioned in this invention are calculated as 25±2℃.

[0020] All raw materials used in this invention can be obtained commercially or prepared using existing technologies.

[0021] This invention provides a bupivacaine-meroxicam sustained-release solution comprising the following components in parts by weight: 2-3 parts of bupivacaine or a pharmaceutically acceptable salt thereof, 0.05-0.1 parts of meloxicam or a pharmaceutically acceptable salt thereof, 5-20 parts of ethyl cellulose, 20-45 parts of triacetin, 30-45 parts of dimethyl sulfoxide, 0.03-0.07 parts of maleic acid, and 0.03-0.07 parts of butylated hydroxytoluene.

[0022] The bupivacaine meloxicam sustained-release solution of the present invention comprises 2 to 3 parts of bupivacaine or a pharmaceutically acceptable salt thereof, for example, 2 parts, 2.5 parts or 3 parts, etc.

[0023] The bupivacaine meloxicam sustained-release solution of the present invention comprises 0.05 to 0.1 parts of meloxicam or a pharmaceutically acceptable salt thereof, for example, 0.05 parts, 0.075 parts or 0.1 parts, etc.

[0024] The bupivacaine meloxicam sustained-release solution of the present invention comprises 5 to 20 parts of ethyl cellulose, for example, 5 parts, 10 parts, 15 parts or 20 parts, etc.

[0025] The bupivacaine meloxicam sustained-release solution of the present invention comprises 20 to 45 parts of triacetin, for example, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts or 45 parts, etc.

[0026] The bupivacaine meloxicam sustained-release solution of the present invention comprises 30 to 45 parts of dimethyl sulfoxide, for example, 30 parts, 32 parts, 35 parts, 40 parts or 45 parts, etc.

[0027] The bupivacaine meloxicam sustained-release solution of the present invention comprises 0.03 to 0.07 parts of maleic acid, for example, 0.03 parts, 0.04 parts, 0.05 parts, 0.06 parts or 0.07 parts, etc.

[0028] The bupivacaine meloxicam sustained-release solution of the present invention comprises 0.03 to 0.07 parts of butylated hydroxytoluene, for example, 0.03 parts, 0.04 parts, 0.05 parts, 0.06 parts or 0.07 parts.

[0029] In this invention, the viscosity of the ethyl cellulose is 18~110 mPa·s, for example, it can be 18~22 mPa·s, 45~60 mPa·s, 90~110 mPa·s, etc.

[0030] In this invention, the viscosity of the ethyl cellulose is 18~22 mPa·s.

[0031] In this invention, the viscosity of the ethyl cellulose is 90~110 mPa·s.

[0032] In this invention, the components include the following parts by weight: 2-3 parts of bupivacaine or a pharmaceutically acceptable salt thereof, 0.05-0.1 parts of meloxicam or a pharmaceutically acceptable salt thereof, 15-20 parts of ethyl cellulose, 20-45 parts of triacetin, 30-45 parts of dimethyl sulfoxide, 0.03-0.07 parts of maleic acid, and 0.03-0.07 parts of butylated hydroxytoluene.

[0033] The present invention also provides a method for preparing the above-mentioned bupivacaine meloxicam sustained-release solution, characterized by comprising the following steps: (1) Ethyl cellulose and triacetin were mixed in parts by mass to obtain a polymer phase; (2) By mass fractions, bupivacaine or a pharmaceutically acceptable salt thereof, meloxicam or a pharmaceutically acceptable salt thereof, maleic acid, butylated hydroxytoluene and dimethyl sulfoxide are mixed to obtain the drug phase; (3) Mix the drug phase and the polymer phase to obtain a bupivacaine meloxicam sustained-release solution.

[0034] The preparation method of the present invention is simple, and the prepared bupivacaine meloxicam sustained-release solution is in a homogeneous solution state. It does not require complex emulsification, homogenization or microsphere preparation processes, and its production process is easy to control and scale up, which meets the requirements of industrial production.

[0035] Step (1) of the present invention is to mix ethyl cellulose and triacetin and stir at 50~70°C until the ethyl cellulose is completely dissolved to form a transparent polymer phase.

[0036] In this invention, the mixing temperature in step (1) is 50~70℃, for example, it can be 50℃, 55℃, 60℃, 65℃ or 70℃.

[0037] Step (2) of the present invention involves dissolving bupivacaine or a pharmaceutically acceptable salt thereof, meloxicam or a pharmaceutically acceptable salt thereof, maleic acid and butylated hydroxytoluene in dimethyl sulfoxide and stirring until completely dissolved to form a drug phase.

[0038] Step (3) of this invention involves slowly adding the drug phase to the polymer phase under continuous stirring, maintaining the system temperature at 40~60℃, continuing stirring until the mixed solution is homogeneous, and then cooling to room temperature.

[0039] In a preferred embodiment of the present invention, the homogeneous solution obtained by mixing the drug phase and the polymer phase is cooled, filtered and sterilized, and then filled to obtain the finished product of bupivacaine meloxicam sustained-release solution.

[0040] In a preferred embodiment of the present invention, filtration sterilization is performed using a 0.22 μm microporous filter membrane.

[0041] In a preferred embodiment of the present invention, filling is performed in a pre-filled syringe or vial.

[0042] In this invention, the mixing temperature in step (3) is 40~60℃, for example, it can be 40℃, 45℃, 50℃, 55℃ or 60℃.

[0043] The present invention also provides the use of the above-mentioned bupivacaine meloxicam sustained-release solution in the preparation of a medicament for the prevention or treatment of postoperative pain.

[0044] The bupivacaine-meloxicam sustained-release solution of this invention exhibits excellent long-term stability. During a 6-month long-term storage test and a 3-month accelerated test, the active pharmaceutical ingredient content did not decrease significantly, the content of related substances remained at extremely low levels with a slow rate of increase, and the key physicochemical properties and release behavior remained stable. These results validate that the formulation design based on ethyl cellulose and combined with the BHT antioxidant can effectively ensure the quality of the compound preparation during storage, meeting the stringent requirements for formulation stability stipulated in drug registration regulations.

[0045] The core feature of this invention is the use of ethyl cellulose as a sustained-release carrier. This method effectively avoids the protection scope centered on PLGA, PCL, polyorthoesters, etc., and has the possibility of free implementation.

[0046] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0047] Example 1 The sustained-release solution is composed of the following raw materials in parts by mass: 2.5 parts bupivacaine, 0.075 parts meloxicam, 20.0 parts ethyl cellulose (viscosity 18~22 mPa·s), 45.0 parts triacetin, 32.325 parts dimethyl sulfoxide, 0.05 parts maleic acid and 0.05 parts butylated hydroxytoluene.

[0048] Preparation method of sustained-release solution: (1) Weigh 20.0g of ethyl cellulose and 45.0g of triacetyl ester and place them in a container with a stirrer. Heat in a water bath at 60°C and stir at 200 rpm for about 2 hours until the ethyl cellulose is completely dissolved to obtain a clear and transparent polymer phase.

[0049] (2) In another container, 2.5g bupivacaine, 0.075g meloxicam, 0.05g maleic acid and 0.05g butylated hydroxytoluene were added to 32.325g dimethyl sulfoxide in sequence and stirred magnetically at room temperature until all solutes were completely dissolved to obtain the drug phase.

[0050] (3) While stirring continuously, slowly add the drug phase to the polymer phase which is kept at a constant temperature of 50°C.

[0051] (4) After the addition is complete, keep the temperature at 50°C and continue stirring for 1 hour to obtain a homogeneous, transparent, viscous solution.

[0052] (5) Cool the solution to about 25°C and filter it through a 0.22μm PTFE membrane for sterilization.

[0053] (6) Under aseptic conditions, the filtered solution is filled into a 1 mL pre-filled syringe to obtain bupivacaine meloxicam sustained-release solution.

[0054] Example 2 The sustained-release solution is composed of the following raw materials by mass fraction: 2.5 parts bupivacaine, 0.075 parts meloxicam, 15.0 parts ethyl cellulose (viscosity 90~110 mPa·s), 45.0 parts triacetin, 37.325 parts dimethyl sulfoxide, 0.05 parts maleic acid and 0.05 parts butylated hydroxytoluene.

[0055] The preparation method is the same as in Example 1.

[0056] Example 3 The sustained-release solution is composed of the following raw materials by mass fraction: 2.5 parts bupivacaine, 0.075 parts meloxicam, 20.0 parts ethyl cellulose (viscosity 45~60 mPa·s), 40.0 parts triacetin, 37.325 parts dimethyl sulfoxide, 0.05 parts maleic acid and 0.05 parts butylated hydroxytoluene.

[0057] The preparation method is the same as in Example 1.

[0058] Comparative Example 1 The only difference from Example 1 is that ethyl cellulose is omitted, and the amount of dimethyl sulfoxide is adjusted to 52.325 parts.

[0059] Comparative Example 2 The only difference from Example 1 is that butylated hydroxytoluene is omitted, and the amount of dimethyl sulfoxide is adjusted to 32.375 parts.

[0060] In vitro release test Take appropriate amounts of the sustained-release solutions prepared in Examples 1-3 and Comparative Examples 1-2 (equivalent to 5 mg of bupivacaine), place them in dialysis cups, and then place them in release tubes containing 4 mL of physiological saline. Conduct release experiments in a constant-temperature shaking water bath at 37°C and 100 rpm. At predetermined time points (0.5, 1, 2, 3, 6, 12, 24, 48, 72 hours), take 1 mL samples (with simultaneous addition of isothermal and equal-volume fresh physiological saline). Determine the concentrations of bupivacaine and meloxicam using high-performance liquid chromatography (HPLC) and calculate the cumulative release rate. Plot the results as release curves. The release curve for Example 1 is shown below. Figure 1 As shown in the figure. The results showed that the sustained-release solution exhibited typical sustained-release characteristics in the in vitro release medium, with a burst release of less than 20% within 2 hours, and a cumulative release of more than 85% for both bupivacaine and meloxicam within 48 hours, demonstrating good simultaneous sustained-release properties.

[0061] Stability study data Accelerated stability and long-term stability tests were conducted on the bupivacaine-meloxicam sustained-release solutions prepared in Examples 1-3 and Comparative Examples 1-2. Samples were filled into 1 mL colorless, transparent pre-filled glass syringes, stopped with brominated butyl rubber stoppers, and examined under specific temperature conditions. The results are shown in the table below: Table 1: Accelerated stability test results (conditions: 40℃±2℃, 75%±5%)

[0062] Conclusion: After being placed under accelerated testing conditions for 3 months, the key quality attributes of the three batches of samples in Examples 1-3, including content, related substances and release behavior, did not change significantly, indicating that the product has good stability under high temperature and high humidity conditions.

[0063] Table 2: Results of long-term stability test (conditions: 25℃±2℃, 60%±5% RH)

[0064] Conclusion: After being placed under long-term experimental conditions for 6 months, all indicators of all samples in Examples 1-3 met the preset standards. The growth rate of related substances was relatively slow, and the release curve remained stable. This fully demonstrates that the bupivacaine meloxicam sustained-release solution of the present invention has excellent chemical and physical stability under normal storage conditions, and its shelf life is predicted to be more than 24 months.

[0065] In vivo pharmacodynamic studies in animals To verify the long-lasting analgesic effect and drug release characteristics of the sustained-release solution of the present invention in vivo, an in vivo pharmacodynamic study was conducted using an SD rat postoperative pain model.

[0066] Experimental Methods: Forty male SD rats (180-220g) were randomly divided into four groups (n=10): negative control group (physiological saline), positive control group (ordinary bupivacaine-meroxicam solution, without ethylcellulose and triacetin, other components the same), Example 1 group, and Comparative Example 1 group (without ethylcellulose). A postoperative pain model was established in all rats by incision of the right hind paw. Immediately after surgery, the corresponding preparation (dose of bupivacaine 2.5mg / kg) was subcutaneously injected around the incision site. The mechanical pain threshold was measured using Von Frey fibers at 0.5h, 1h, 2h, 3h, 6h, 12h, 24h, 48h, and 72h after administration. Three rats from each group were sacrificed at the same time point, and tissue homogenates from the injection site were analyzed by HPLC to determine the concentrations of bupivacaine and meloxicam.

[0067] Results of release into the body: Table 3: In vivo release results (bupivacaine tissue concentration, μg / g)

[0068] Table 4: In vivo release results (meloxicam tissue concentration, μg / g)

[0069] In the positive control group, drug absorption was rapid, with peak concentrations of bupivacaine appearing at 2 hours (15.8 μg / g) and meloxicam at 2 hours (0.40 μg / g), followed by a rapid decline. By 24 hours, bupivacaine had decreased to 1.2 μg / g, and it became undetectable after 48 hours. In Example 1 group, both drugs were released stably, remaining detectable at 72 hours (bupivacaine 2.1 μg / g, meloxicam 0.06 μg / g), maintaining effective concentrations for over 72 hours. The release behavior of Comparative Example 1 (without ethylcellulose) was similar to the positive control group, with no significant sustained-release effect.

[0070] Table 5: Efficacy Results (Percentage of Pain Threshold, Normalized to Baseline)

[0071] Results: In Example 1, the analgesic effect began to appear 0.5 hours after administration, reaching a peak of >82% between 2 and 6 hours, maintaining 78% at 24 hours, 68% at 48 hours, and 62% at 72 hours. This was significantly higher than that of the positive control group (only 38% at 72 hours) and Comparative Example 1 (only 36% at 72 hours), demonstrating rapid onset and long-lasting stable analgesic properties (lasting for more than 72 hours). Comparative Example 1 (without ethyl cellulose) lost its sustained-release effect, and the analgesic effect rapidly diminished after 12 hours, further demonstrating that ethyl cellulose is a key excipient for achieving long-acting release.

[0072] Conclusion: The sustained-release solution of this invention can continuously release bupivacaine and meloxicam in rats for more than 72 hours and produce corresponding long-lasting analgesic effects. The in vivo behavior is consistent with the trend of the in vitro release test results.

[0073] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A bupivacaine-meloxicam sustained-release solution, characterized in that, It comprises the following components in parts by weight: 2-3 parts of bupivacaine or a pharmaceutically acceptable salt thereof, 0.05-0.1 parts of meloxicam or a pharmaceutically acceptable salt thereof, 5-20 parts of ethyl cellulose, 20-45 parts of triacetin, 30-45 parts of dimethyl sulfoxide, 0.03-0.07 parts of maleic acid and 0.03-0.07 parts of butylated hydroxytoluene.

2. The bupivacaine meloxicam sustained-release solution according to claim 1, characterized in that, The viscosity of the ethyl cellulose is 18~110 mPa·s.

3. The bupivacaine meloxicam sustained-release solution according to claim 1, characterized in that, The viscosity of the ethyl cellulose is 18~22 mPa·s.

4. The bupivacaine meloxicam sustained-release solution according to claim 1, characterized in that, The viscosity of the ethyl cellulose is 90~110 mPa·s.

5. The bupivacaine meloxicam sustained-release solution according to claim 1, characterized in that, It comprises the following components in parts by weight: 2-3 parts of bupivacaine or a pharmaceutically acceptable salt thereof, 0.05-0.1 parts of meloxicam or a pharmaceutically acceptable salt thereof, 15-20 parts of ethyl cellulose, 20-45 parts of triacetin, 30-45 parts of dimethyl sulfoxide, 0.03-0.07 parts of maleic acid and 0.03-0.07 parts of butylated hydroxytoluene.

6. A method for preparing a bupivacaine-meloxicam sustained-release solution according to any one of claims 1 to 5, characterized in that, Includes the following steps: (1) Ethyl cellulose and triacetin were mixed in parts by mass to obtain a polymer phase; (2) By mass fractions, bupivacaine or a pharmaceutically acceptable salt thereof, meloxicam or a pharmaceutically acceptable salt thereof, maleic acid, butylated hydroxytoluene and dimethyl sulfoxide are mixed to obtain the drug phase; (3) Mix the drug phase and the polymer phase to obtain a bupivacaine meloxicam sustained-release solution.

7. The preparation method according to claim 6, characterized in that, The mixing temperature in step (1) is 50~70℃.

8. The preparation method according to claim 6, characterized in that, The mixing temperature in step (3) is 40~60℃.

9. The use of the bupivacaine meloxicam sustained-release solution according to any one of claims 1 to 5 in the preparation of a medicament for the prevention or treatment of postoperative pain.

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